Nonobese diabetic (NOD) mice spontaneously develop autoimmune diabetes. The disease is characterized by T cell orchestrated progressive infiltration of the islets (insulitis) by lymphocytes and macrophages leading to overt diabetes. Numerous investigators have identified treatments that prevent the development of diabetes in NOD mice. However, restoration of normal islet cell morphology and resolution of the T cell rich, infiltrative autoimmune insulitis is far more difficult and has been achieved with only very few therapies. Even more challenging is the restoration of a euglycemic state in mice that have developed frank diabetes. Only one satisfactory treatment, anti- CD3 mAb, has been developed that halts albeit temporarily, the progression from new onset to permanent diabetes in man. Therefore, it may prove useful to identify therapies able to reverse established autoimmunity in mice as means to identify new strategies for clinical testing. To this end we are now proposing study of a regimen that is aimed at selective destruction of diabetogenic, autoimmune T cells while sparing regulatory T (Treg) from comparable loss, thereby tipping the balance from autoimmunity to immune protection. We have developed a novel strategy that includes agonist (wild type) IL-2/Fc fusion protein as a component to enhance AICD; a high affinity IL-15Ralpha antagonist mutant IL-15/Fc fusion protein (mIL-15/Fc) to block proliferative and anti-apoptotic IL-15 signals as a component to harness PCD; and rapamycin (RPM) to antagonize the proliferative response of activated T cells to T cell growth factors (TCGF) without inhibiting the AICD signal imparted by EL-2. Moreover, the agonist IL-2 and antagonist IL-15 related proteins were designed as IgG 2a derived Fc fusion proteins to ensure a prolonged circulating half-life and also provide a potential means to kill activated IL-2R+ and IL-15R+ target cells via complement dependent (CDC) and antibody dependent (ADCC) cell cytotoxicity activating. This strategy has proven useful in extremely stringent transplant models, including a model in which allogeneic T cells are transplanted into diabetic NOD mice. The objective of this project is to further explore the utility of this treatment method to restore euglycemia in new onset, spontaneously diabetic autoimmune NOD mice. We hope that our approach will lead to a better understanding of the mechanisms that generate and maintain tolerance to islet beta cells and to establish models that will examine the interaction of the immune system and beta-cell turnover within islets during the invasive stages of the autoimmune process. The ultimate goal is to develop a safe and effective strategy for the treatment and potential cure of early onset of T1DM in human.